Functional analysis of NK cells and their potential to generate CTL responses Natural Killer (NK) cells detect and kill pathogen-infected host cells, as well as neoplastic cells and tissue allografts. However, recent work in our laboratory suggests that they discharge another duty as well: one that establishes a strong tie between NK cells and their relatives in the adaptive immune system. By inducing apoptosis of cells that exhibit missing self, NK cells prompt a strong CD8+ T, CD4+ T and B cell response. The adaptive immune responses via this pathway are significantly amplified compared to immune responses observed after immunization with 3-irradiated cells. While in previous studies, we found that the adaptive immune responses induced by 3-irradiated cells occurred independent of MyD88/Trif signaling, the responses induced by NK cell- mediated cell death-particularly the amplification observed in this pathway-requires a MyD88/Trif-dependent component. Further studies in vitro, have revealed that lymphoid DCs release increased levels of IL-12 when exposed to cells rendered apoptotic by Fas- ligation (but not when exposed to 3-irradiated cells), suggesting that IL-12 production and subsequent MyD88 pathway signaling could be responsible for the amplification observed in this pathway. In the current proposal, we aim to understand the underlying molecular mechanisms and biological consequences of: (a) the contributions of NK cell- specific pathways to the generation of robust CD8+ T cell responses; (b) the DC-specific activation pathways induced by (NK cell-mediated) cell death that drive CD8+ T cell responses. Finally (c), we aim to understand the underlying molecular mechanisms and biological consequences of CD4+ T and B cell responses driven by this pathway. Ultimately, this newly identified function of NK cells may have important implications for a wide variety of diseases, and may be exploited in the design of effective vaccines that promote strong cell-mediated and humoral immunity. PUBLIC HEALTH RELEVANCE: We believe that the NK->DC->T/B cell axis represents a fundamental pathway for the generation of robust adaptive immune responses that may provide a unique and powerful strategy for vaccine development. In addition, a better understanding of this pathway may be essential to provide insight into the development and/or control of a wide variety of diseases, including viral/bacterial infections, autoimmunity, and/or neoplastic diseases.